Current approaches to characterize micro- and macroscale circuit mechanisms of Parkinson's disease in rodent models.

Accelerating technological progress in experimental neuroscience is increasing the scale as well as specificity of both observational and perturbational approaches to study circuit physiology. While these techniques have also been used to study disease mechanisms, a wider adoption of these approaches in the field of experimental neurology would greatly facilitate our understanding of neurological dysfunctions and their potential treatments at cellular and circuit level. In this review, we will introduce classic and novel methods ranging from single-cell electrophysiological recordings to state-of-the-art calcium imaging and cell-type specific optogenetic or chemogenetic stimulation. We will focus on their application in rodent models of Parkinson's disease while also presenting their use in the context of motor control and basal ganglia function. By highlighting the scope and limitations of each method, we will discuss how they can be used to study pathophysiological mechanisms at local and global circuit levels and how novel frameworks can help to bridge these scales.

Author Correction: Transneuronal propagation of mutant huntingtin contributes to non-cell autonomous pathology in neurons.

In the version of this article initially published, the catalog numbers for BoNT A and B were given in the Methods section as T0195 and T5644; the correct numbers are B8776 and B6403. The error has been corrected in the HTML and PDF versions of the article.

Midbrain circuits for defensive behaviour.

Survival in threatening situations depends on the selection and rapid execution of an appropriate active or passive defensive response, yet the underlying brain circuitry is not understood. Here we use circuit-based optogenetic, in vivo and in vitro electrophysiological, and neuroanatomical tracing methods to define midbrain periaqueductal grey circuits for specific defensive behaviours. We identify an inhibitory pathway from the central nucleus of the amygdala to the ventrolateral periaqueductal grey that produces freezing by disinhibition of ventrolateral periaqueductal grey excitatory outputs to pre-motor targets in the magnocellular nucleus of the medulla. In addition, we provide evidence for anatomical and functional interaction of this freezing pathway with long-range and local circuits mediating flight. Our data define the neuronal circuitry underlying the execution of freezing, an evolutionarily conserved defensive behaviour, which is expressed by many species including fish, rodents and primates. In humans, dysregulation of this 'survival circuit' has been implicated in anxiety-related disorders.

Transneuronal propagation of mutant huntingtin contributes to non-cell autonomous pathology in neurons.

In Huntington's disease (HD), whether transneuronal spreading of mutant huntingtin (mHTT) occurs and its contribution to non-cell autonomous damage in brain networks is largely unknown. We found mHTT spreading in three different neural network models: human neurons integrated in the neural network of organotypic brain slices of HD mouse model, an ex vivo corticostriatal slice model and the corticostriatal pathway in vivo. Transneuronal propagation of mHTT was blocked by two different botulinum neurotoxins, each known for specifically inactivating a single critical component of the synaptic vesicle fusion machinery. Moreover, healthy human neurons in HD mouse model brain slices displayed non-cell autonomous changes in morphological integrity that were more pronounced when these neurons bore mHTT aggregates. Altogether, our findings suggest that transneuronal propagation of mHTT might be an important and underestimated contributor to the pathophysiology of HD.

Brainstem nucleus MdV mediates skilled forelimb motor tasks.

Translating the behavioural output of the nervous system into movement involves interaction between brain and spinal cord. The brainstem provides an essential bridge between the two structures, but circuit-level organization and function of this intermediary system remain poorly understood. Here we use intersectional virus tracing and genetic strategies in mice to reveal a selective synaptic connectivity matrix between brainstem substructures and functionally distinct spinal motor neurons that regulate limb movement. The brainstem nucleus medullary reticular formation ventral part (MdV) stands out as specifically targeting subpopulations of forelimb-innervating motor neurons. Its glutamatergic premotor neurons receive synaptic input from key upper motor centres and are recruited during motor tasks. Selective neuronal ablation or silencing experiments reveal that MdV is critically important specifically for skilled motor behaviour, including accelerating rotarod and single-food-pellet reaching tasks. Our results indicate that distinct premotor brainstem nuclei access spinal subcircuits to mediate task-specific aspects of motor programs.

Motor-circuit communication matrix from spinal cord to brainstem neurons revealed by developmental origin.

Accurate motor-task execution relies on continuous comparison of planned and performed actions. Motor-output pathways establish internal circuit collaterals for this purpose. Here we focus on motor collateral organization between spinal cord and upstream neurons in the brainstem. We used a newly developed mouse genetic tool intersectionally with viruses to uncover the connectivity rules of these ascending pathways by capturing the transient expression of neuronal subpopulation determinants. We reveal a widespread and diverse network of spinal dual-axon neurons, with coincident input to forelimb motor neurons and the lateral reticular nucleus (LRN) in the brainstem. Spinal information to the LRN is not segregated by motor pool or neurotransmitter identity. Instead, it is organized according to the developmental domain origin of the progenitor cells. Thus, excerpts of most spinal information destined for action are relayed to supraspinal centers through exquisitely organized ascending connectivity modules, enabling precise communication between command and execution centers of movement.